Diaminotrifluoromethylpyridine derivatives, process for their production and phospholipase A2 inhibitor containing them

ABSTRACT

A method of treating rheumatoid arthritis using a diaminotrifluoromethylpyridine derivative of the formula (I) or its salt: ##STR1## wherein X is --CW 1  R 1 , --COCOR 2 , --CW 1  NHCOR 2 , --C(═W 1 )W 2  R 3  or --CW 1  N(R 4 )R 5 , and Y is alkyl, --CW 3  R 6 , --COCOR 7 , --NHCOR 7 , --C(═W 3 )W 4  R 8 , --(NH) m  SO 2  R 9 , --(NH) m  SO 2  OR 10  or --(NH) m  SO 2  N(R 11 )R 12 , wherein each of R 1 , R 6  and R 9 , which are independent from one another, is a chain hydrocarbon group which may be substituted, a monocyclic hydrocarbon group which may be substituted, a polycyclic hydrocarbon group which may be substituted, a monocyclic heterocycle group which may be substituted or a polycyclic heterocycle group which may be substituted as further defined herein.

This is a division of application Ser. No. 08/035,622, filed on Mar. 23, 1993 now U.S. Pat. No. 5,348,967, which is a division of application Ser. No. 07/723,377, filed on Jun. 28, 1991, now U.S. Pat. No. 5,229,403.

The present invention relates to novel diaminotrifluoromethylpyridine derivatives of their salts, a process for their production, a phospholipase A₂ inhibitor, an anti-inflammatory agent and an anti-pancreatitis agent containing them, and novel trifluoromethylpyridine derivatives as intermediates.

As a diaminotrifluoromethylpyridine derivative, for example, U.S. Pat. Nos. 3,746,531 and 3,962,263 disclose a pyridine as an active ingredient of a herbicide, which has trifluoromethyl at the 5-position, --NHCO--CF₂ --T¹ wherein T¹ is a hydrogen atom, a chlorine atom, a fluorine atom, alkyl or haloalkyl at either the 2-position or the 3-position, and --NHCO--CF₂ --T² wherein T² is a hydrogen atom, a chlorine atom, a fluorine atom, alkyl, haloalkyl or alkylcarbonyl, or --NHCOOT³ wherein T³ is C₁₋₄ lower alkyl or phenyl at the other position. However, this is different in the chemical structure from the diaminotrifluoromethylpyridine derivative of the present invention. Further, U.S. Pat. No. 3,961,063 discloses a trifluoromethyl-substituted pyridine as an active ingredient of an anthelmintic, which has --NHCSNHCOT⁴ wherein T⁴ is alkoxy, at the 2- and 3-positions. However, this compound is different in the chemical structure from the diaminotrifluoromethylpyridine derivative of the present invention.

The present invention provides a diaminotrifluoromethylpyridine derivative of the formula (I) or its salt: ##STR2## wherein X is --CW¹ R¹, --COCOR², --CW¹ NHCOR², --C(═W¹)W² R³ or --CW¹ N(R⁴)R⁵, and Y is alkyl, --CW³ R⁶, --COCOR⁷, --NHCOR⁷, --C(═W³)W⁴ R⁸, --(NH)_(m) SO₂ R⁹, --(NH)_(m) SO₂ OR¹⁰ or --(NH)_(m) SO₂ N(R¹¹)R¹², wherein each of R¹, R⁶ and R⁹, which are independent from one another, is a chain hydrocarbon group which may be substituted, a monocyclic hydrocarbon group which may be substituted, a polycyclic hydrocarbon group which may be substituted, a monocyclic heterocycle group which may be substituted or a polycyclic heterocycle group which may be substituted, each of R² and R⁷, which are independent from each other, is alkyl which may be substituted, alkoxy which may be substituted, phenyl which may be substituted or phenoxy which may be substituted, each of R³, R⁸ and R¹⁰, which are independent from one another, is alkyl which may be substituted, alkenyl which may be substituted, alkynyl which may be substituted, cycloalkyl which may be substituted, phenyl which may be substituted or benzyl which may be substituted, each of R⁴, R⁵, R¹¹ and R¹², which are independent from one another, is alkyl which may be substituted, each of W¹, W², W³ and W⁴, which are independent from one another, is an oxygen atom or a sulfur atom, and m is 0 or 1, provided that a combination wherein one of X and Y is --COCF₂ X¹ wherein X¹ is a hydrogen atom, a halogen atom, alkyl or haloalkyl, and the other is --COCF₂ X² wherein X² is a hydrogen atom, a halogen atom, alkyl, haloalkyl or alkylcarbonyl, or --COOX³ wherein X.sup. 3 is alkyl which may be substituted or phenyl which may be substituted, is excluded; a process for its production; a phospholipase A₂ inhibitor, an anti-inflammatory agent and an anti-pancreatitis agent containing it, and a trifluoromethylpyridine derivative as an intermediate.

Now, the present invention will be described in detail with reference to the preferred embodiments.

In the formula (I), the chain hydrocarbon group for each of R¹, R⁶ and R⁹ may be alkyl, alkenyl or alkynyl. The monocyclic hydrocarbon group may be cycloalkyl, cycloalkenyl or phenyl. The polycyclic hydrocarbon group may be a condensed polycyclic hydrocarbon group such as naphthyl, tetrahydronaphthyl or indanyl, or a bridged polycyclic hydrocarbon group such as adamantyl, noradamantyl, norbornanyl or norbornanonyl. The monocyclic heterocycle group may be pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolinyl, pyrrolidinyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, pyrazolinyl, hydantoinyl, oxazolinyl, isoxazolinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, dioxolanyl, dithiolanyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, dihydropyridyl, tetrahydropyridyl, piperidinyl, dihydrooxopyridazinyl, tetrahydrooxopyridazinyl, dihydrooxopyrimidinyl, tetrahydrooxopyrimidinyl, piperazinyl, dihydropyranyl, tetrahydropyranyl, dioxanyl, dihydrodithinyl, dithianyl or morphorinyl. The polycyclic heterocycle group may be a condensed polycyclic heterocycle group such as thienothienyl, dihydrocyclopentathienyl, indolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzimidazolyl, tetrahydrobenzothienyl, dihydrobenzofuranyl, tetrahydrobenzisoxazolyl, benzodioxolyl, quinolinyl, isoquinolinyl, benzodiaxanyl or quinoxalinyl, or a bridged polycyclic heterocycle group such as quinuclidinyl.

The substituent for each of the chain hydrocarbon group which may be substituted for each of R¹, R⁶ and R⁹, the alkyl which may be substituted and the alkoxy which may be substituted for each of R² and R⁷, the alkyl which may be substituted, the alkenyl which may be substituted and the alkynyl which may be substituted for each of R³, R⁸ and R¹⁰, the alkyl which may be substituted for each of R⁴, R⁵, R¹¹ and R¹² and the alkyl which may be substituted for X³, may be a halogen atom, alkoxy, haloalkoxy, alkylthio, cycloalkyl, cycloalkoxy, cycloalkenyl, cycloalkenyloxy, alkoxycarbonyl, alkylcarbonyl, alkylcarbonyloxy, aryl, aryloxy, arylthio, amino or alkyl-substituted amino. The number of such substituents or substituents on such substituents may be one or more. When the number is two or more, such substituents may be the same or different.

The substituent for each of the monocyclic hydrocarbon group which may be substituted, the polycyclic hydrocarbon group which may be substituted, the monocyclic heterocycle group which may be substituted and the polycyclic heterocycle group which may be substituted for each of R¹, R⁶ and R⁹, the phenyl which may be substituted and the phenoxy which may be substituted for each of R² and R⁷, the cycloalkyl which may be substituted, the phenyl which may be substituted and the benzyl which may be substituted for each of R³, R⁸ and R¹⁰, and the phenyl which may be substituted for X³, may be a halogen atom, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, cycloalkyl, cycloalkoxy, cycloalkenyl, cycloalkenyloxy, alkoxycarbonyl, alkycarbonyl, alkylcarbonyloxy, aryl, aryloxy, arylthio, amino, alkyl-substituted amino, cyano or nitro. The number of such substituents or substituents for such substituents may be one or more. If the number is two or more, such substituents may be the same or different.

In the formula (I), the alkyl group and the alkyl moiety contained in each of X and Y may be C₁₋₁₈ alkyl such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, decyl or nonadecyl, and they include linear or branched aliphatic structural isomers. The alkenyl group and the alkenyl moiety contained in each of X and Y may be C₂₋₁₈ alkenyl such as vinyl, propenyl, butenyl, pentenyl, hexenyl, decenyl or nonadecenyl, and they include linear or branched aliphatic structural isomers. The alkynyl group and the alkynyl moiety contained in each of X and Y may be C₂₋₁₈ alkynyl such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, decynyl or nonadecynyl, and they include linear or branched aliphatic structural isomers. The cycloalkyl group and the cycloalkyl moiety contained in each of X and Y may be C₃₋₈ cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclooctyl. The cycloalkenyl group and the cycloalkenyl moiety contained in each of X and Y my be C₅₋₈ cycloalkenyl such as cyclopentenyl, cyclohexenyl or cyclooctenyl. The halogen atom contained in each of X and Y may be a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. The aryl group and the aryl moiety contained in each of X and Y may be phenyl, thienyl, furanyl, pyridyl, naphthyl, benzothienyl, benzofuranyl or quinolinyl.

Now, preferred embodiments of the compound of the present invention will be described. In the formula (I), it is preferred that X is --CW¹ R¹ or --C(═W¹)W² R³, and Y is --SO₂ R⁹. Each of R¹ and R⁶ is preferably alkyl which may be substituted, alkenyl which may be substituted, cycloalkyl which may be substituted, cycloalkenyl which may be substituted, phenyl which may be substituted, tetrahydronaphthyl which may be substituted, indanyl which may be substituted or thienyl which may be substituted, more preferably, alkyl, haloalkyl, alkenyl, haloalkenyl, cycloalkyl, halogen-substituted cycloalkyl, phenyl, halogen-substituted phenyl, alkyl- or haloalkyl-substituted phenyl, or alkoxy- or haloalkoxy-substituted phenyl. Each of R² and R⁷ is preferably alkoxy which may be substituted or phenyl which may be substituted, more preferably alkoxy, haloalkoxy, phenyl, or halogen-substituted phenyl. Each of R³, R⁸ and R¹⁰ is preferably alkyl which may be substituted, more preferably, alkyl or haloalkyl. Each of R⁴, R⁵, R¹¹ and R¹² is preferably alkyl. R⁹ is preferably alkyl which may be substituted, alkenyl which may be substituted, cycloalkyl which may be substituted, cycloalkenyl which may be substituted or phenyl which may be substituted, more preferably alkyl, haloalkyl, phenyl, halogen-substituted phenyl, alkyl- or haloalkyl-substituted phenyl, or alkoxy- or haloalkoxy-substituted phenyl.

Preferred specific compounds of the present invention include N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl) cyclohexanecarboxamide, N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-5-indanecarboxamide, N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)acetoxyacetamide, N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)crotonamide, N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-2-thiophenecarboxamide, N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-3-trifluoromethylbenzamide, N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)-3-fluorobenzamide, N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-6-(1,2,3,4-tetrahydronaphthalene) carboxamide, N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl) crotonamide, N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-3-(2-thienyl) acrylamide, and their salts.

The compound of the formula (I) may form a salt when Y is --SO₂ R⁹ wherein R⁹ is as defined above. Such a salt may be any pharmaceutically acceptable salt, for example, an alkali metal salt such as a potassium salt or a sodium salt, an alkaline earth metal salt such as a calcium salt, or an organic amine salt such as a triethanol amine salt or a tris(hydroxmethyl)aminomethane salt. Such a salt may have crystal water.

The compounds of the formula (I) and (I-1) can be prepared, for example, by processes represented by the following reactions (A) and (B): ##STR3##

In the above formulas, R¹, R², R³, R⁴, R⁵, W¹, W², X and Y are as defined above, and Z is a halogen atom. ##STR4##

In the above formulas Y¹ is --CW³ R⁶, --COCOR⁷ or --C(═W³) W⁴ R⁸, wherein R⁶, R⁷, R⁸, W³, W⁴, X and Z are as defined above.

A compound of the formula (I-1) wherein X and Y¹ are the same substituents, can be prepared in the same manner as the Reaction (B) using as the starting material 2,3-diamino-5-trifluoromethylpyridine instead of the compound of the formula (III).

The reactions (A) and (B) are usually conducted in the presence of a solvent, if necessary, by using a base. The solvent may be an aromatic hydrocarbon such as benzene, toluene, xylene or chlorobenzene; a cyclic or non-cyclic aliphatic hydrocarbon such as chloroform, carbon tetrachloride, methylene chloride, dichloroethane, trichloroethane, n-hexane or cyclohexane; and ether such as diethyl ether, dioxane or tetrahydrofuran; a ketone such as acetone, methyl ethyl ketone or methyl isobutyl ketone; a nitrile such as acetonitrile or propionitrile; an aprotic polar solvent such as dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide or sulfolane. The base may be an inorganic base or an organic base. The inorganic base may, for example, be an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide; and alkali metal or alkaline earth metal carbonate such as anhydrous potassium carbonate or anhydrous calcium carbonate; an alkali metal hydride such as sodium hydride; or an alkali metal such as sodium metal. The organic base may be pyridine or triethylamine.

In the Reactions (A) and (B), a dehydrating condensation agent is required for the reaction with HOOCR¹ or HOOCR⁶. Such a dehydrating condensation agent may be dicyclohexylcarbodiimide, N,N'-carbonyldiimidazole or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. The reaction temperature is usually within a range of -30° to +100° C., preferably from 0° to 60° C., and the reaction time is usually within a range of from 1 to 24 hours, preferably from 1 to 10 hours.

The compound of the formula (II) can be prepared, for example, by processes represented by the following Reactions (C), (D) and (E): ##STR5##

In the above formulas, Y is as defined above.

The amination step in the above Reaction (C) is conducted usually in the presence of a solvent, if necessary, by using a base. The solvent may be an aromatic hydrocarbon such as benzene, toluene, xylene or chlorobenzene; a cyclic or non-cyclic aliphatic hydrocarbon such as chloroform, carbon tetrachloride, methylene chloride, dichloroethane, trichloroethane, n-hexane or cyclohexane; an ether such as diethyl ether, dioxane or tetrahydrofuran; a nitrile such as acetonitrile or propionitrile; or an aprotic polar solvent such as dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide or sulfolane. The base may be the same as the one useful for the above-mentioned Reactions (A) and (B). The reaction temperature is usually within a range of from -30° to +100° C., and the reaction time is usually from 1 to 24 hours.

The reduction reaction in the reduction step in the above Reaction (C) may be conducted by a method wherein an acid such as hydrochloric acid or acetic acid is used together with iron or zinc, a method wherein sodium hydrosulfide, potassium hydrosulfide, sodium sulfide, potassium sulfide or sodium hydrosulfite is used, or a method of catalytic hydrogenation wherein hydrogen is used in the presence of a palladium catalyst or a nickel catalyst. The solvent to be used for the reduction may be optionally selected depending upon the reduction method. Usually, an alcohol such as methanol, ethanol or propanol, water, acetic acid, ethyl acetate, dioxane, tetrahydrofuran or acetonitrile may be employed. The reaction temperature is usually from 0° to 100° C., and reaction temperature is usually from 0° to 100° C., and the reaction time is usually from 1 to 24 hours.

(i) In a case where Y is --CW³ R⁶ or -COCOR⁷ ##STR6##

In the above formulas, Y² is --CW³ R⁶ or --COCOR⁷, wherein R⁶, R⁷, W³ and Z are as defined above.

The protecting group addition step and the Y² -modification step in the above Reaction (D) can be conducted in the same manner as in the above Reactions (A) and (B). Further, the protecting group removal step in the above Reaction (D) can be conducted by catalytic hydrogenation by means of a palladium catalyst such as palladium carbon usually in the presence of a solvent or by the hydrolysis usually in the presence of a solvent and an acid or base. The solvent may be water; an alcohol such as methanol or ethanol; or an ether such as diethyl ether, dioxane or tetrahydrofuran. The acid may be hydrobromic acid or trifluoroacetic acid. The base may be lithium hydroxide, potassium hydroxide, sodium hydroxide, potassium carbonate or sodium carbonate. The reaction temperature is usually from 0° to 100° C., and the reaction time is usually from 1 to 24 hours.

(ii) In a case where Y is --SO₂ R^(9') ##STR7##

In the above formulas, Y³ is --SO₂ R⁹ ', R^(9') is alkyl which may be substituted, alkenyl which may be substituted, cycloalkyl which may be substituted or cycloalkenyl which may be substituted.

The amination step in the above Reaction (E) can be conducted usually in the presence of a solvent by means of a base. The solvent may be an aprotic polar solvent such as dimethyl acetamide, 1,3-dimethyl-2-imidazolidinone or dimethylsulfoxide. The base may be an inorganic base, for example, an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, or an alkali metal carbonate such as anhydrous potassium carbonate or anhydrous sodium carbonate. The reaction temperature is usually from 80° to 150° C., and the reaction time is usually from 1 to 10 hours.

The sulfonyl-modification step in the above Reaction (E) can be conducted in the same manner as in the above Reactions (A) and (B).

The nitration step in the above Reaction (E) can be conducted by reacting with nitric acid or nitrate usually in the presence of a solvent. The nitrate may be sodium nitrate or potassium nitrate. The solvent may be acetic acid, acetic anhydride or trifluoroacetic acid. The reaction temperature is usually from 50° to 120° C., and the reaction time is usually from 1 to 10 hours.

The reduction step in the above Reaction (E) can be conducted in the same manner as the reduction step in the above Reaction (C).

The compound of the above formula (III) can be prepared, for example, by a process represented by the following Reaction (F). ##STR8##

In the above formulas, R¹, R², R³, R⁴, R⁵, W¹, W², X and Z are as defined above.

The above Reaction (F) can be conducted in the same manner as the above Reactions (A) and (B).

Among the compounds of the formula (IV), those wherein Y is --SO₂ R⁹, --SO₂ OR¹⁰ or --SO₂ N(R¹¹)R¹², can be produced also by a process represented by the following Reaction (G). ##STR9##

In the above formulas, Y⁴ is --SO₂ R⁹, --SO₂ OR¹⁰ or --SO₂ N(R¹¹)R¹², wherein R⁹, R¹⁰, R¹¹ and R¹² are as defined above.

The above Reaction (G) can be conducted in the same manner as the sulfonyl-modification step in the above Reaction (E).

The compound of the formula (I) can also be prepared by the following alternative method represented by a Reaction (H). ##STR10##

In the above formulas, R¹, R², R³, R⁴, R⁵, W¹, W², X, Y and Z are as defined above.

The X-modification step in the above Reaction (H) can be conducted in the same manner as the above Reaction (A), and the amination step is conducted in the same manner as the amination step in the above Reaction (C).

Among the compounds of the above formulas (II), (IV), (IV-1), (V), (VI) and (VII), the following compounds are novel compounds and can be produced by the above Reactions (C), (E) and (G).

Trifluoromethylpyridine derivatives of the formula (VIII): ##STR11## wherein Q is a hydrogen atom, nitro or amino, and Y⁵ is --(NH)_(m) --SO₂ R⁹ wherein R⁹ and m are as defined above, --(NH)_(m) --SO₂ OR¹⁰ wherein R¹⁰ and m are as defined above, or --(NH)_(m) --SO₂ N(R¹¹)R¹² wherein R¹¹, R¹² and m are as defined above, provided that when Q is a hydrogen atom and m is 0, R⁹ is other than naphthyl or phenyl which may be substituted.

Now, Preparation Examples for the compounds of the present invention will be described.

PREPARATION EXAMPLE 1

Preparation of N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)pentafluoropropionamide (Compound No. 19)

(1) 3.1 g of ethanesulfonamide was dissolved in 50 ml of dry tetrahydrofuran, and 1.2 g of 60% sodium hydride was added thereto under cooling with ice. After completion of the addition, the mixture was reacted for one hour under reflux. After cooling, 5.0 g of 2-chloro-3-nitro-5-trifluoromethylpyridine was added thereto, and then the mixture was reacted for 7 hours under reflux. After completion of the reaction, the reaction product was poured into 200 ml of water. Undissolved materials in water were extracted with ethyl ether and removed. Then, the aqueous layer was weakly acidified with dilute hydrochloric acid. Precipitated crystals were collected by filtration and dried to obtain 3.6 g of N-(3-nitro-5-trifluoromethyl-2-pyridyl)ethanesulfonamide having a melting point of from 160° to 163° C.

(2) 1.5 g of N-(3-nitro-5-trifluoromethyl-2-pyridyl)ethanesulfonamide obtained in the above step (1) was dissolved in 30 ml of methanol, and 0.2 g of 5% palladium/carbon was added thereto, and a reduction reaction was conducted under a hydrogen pressure overnight under stirring. After completion of the reaction, 5% palladium/carbon was separated by filtration, and the solvent was distilled off under reduced pressure. The obtained crystals were washed with n-hexane and dried to obtain 1.2 g of N-(3-amino-5-trifluoromethyl-2-pyridyl)ethanesulfonamide having a melting point of from 118° to 120° C.

(3) 0.50 g of N-(3-amino-5-trifluoromethyl-2-pyridyl)ethanesulfonamide obtained in the above step (2) was suspended in 10 ml of dry diethyl ether, and 1.15 g of perfluoropropionic anhydride was dropwise added under cooling with ice. After the dropwise addition, the mixture was stirred for one hour and further reacted at room temperature for one hour. After completion of the reaction, the reaction product was poured into ice water and extracted with ethyl acetate. The extract layer was washed with water and dried, and the solvent was distilled off under reduced pressure. The obtained crystals were washed with n-hexane/ethyl ether to obtain 0.58 g of the desired product (Compound No. 19) having a melting point of from 168° to 170° C.

PREPARATION EXAMPLE 2

Preparation of N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-4-fluorobenzamide (Compound No. 10) (1) 4.4 g of methanesulfonamide was dissolved in 70 ml of dry tetrahydrofuran, and 1.9 g of 60% sodium hydride was added thereto under cooling with ice. After completion of the addition, the mixture was reacted for one hour under reflux. After cooling, 7.0 g of 2-chloro-3-nitro-5-trifluoromethylpyridine was added thereto, and the mixture was reacted for 6 hours under reflux. After completion of the reaction, the reaction product was poured into 300 ml of water and washed with ethyl ether. Then, the aqueous layer was weakly acidified with dilute hydrochloric acid. Precipitated crystals were collected by filtration and dried to obtain 5.8 g of N-(3-nitro-5-trifluoromethyl-2-pyridyl)methanesulfonamide having a melting point of from 138° to 139° C.

(2) 4.0 g of N-(3-nitro-5-trifluoromethyl-2-pyridyl)methanesulfonamide obtained in the above step (1) was dissolved in 66 ml of methanol, and 0.4 g of 5% palladium/carbon was added thereto. A reduction reaction was conducted under a hydrogen pressure overnight under stirring. After completion of the reaction, 5% palladium/carbon was separated by filtration, and the solvent was distilled off under reduced pressure. The obtained crystals were washed with n-hexane and dried to obtain 3.2 g of N-(3-amino-5-trifluoromethyl-2-pyridyl)methanesulfonamide having a melting point of from 128° to 130° C.

(3) 0.50 g of N-(3-amino-5-trifluoromethyl-2-pyridyl)methanesulfonamide obtained in the above step (2) was dissolved in 6 ml of dry tetrahydrofuran, and 0.37 g of p-fluorobenzoyl chloride was dropwise added under cooling with ice. After the dropwise addition, the mixture was stirred for one hour and further reacted at room temperature overnight. After completion of the reaction, the reaction product was poured into ice water and extracted with ethyl acetate. The extract layer was washed with water and dried. The solvent was distilled off under reduced pressure, and the residue thereby obtained was crystallized from n-hexane/ethyl ether to obtain 0.61 g of the desired product (Compound No. 10) having a melting point of from 211° to 213° C.

PREPARATION EXAMPLE 3

Preparation of N-(3-trichloroacetylamino-5-trifluoromethyl-2-pyridyl)trifluoroacetamide (Compound No. 30)

(1) Into 38 ml of dry tetrahydrofuran, 1.5 g of 2,3-diamino-5-trifluoromethylpyridine was dissolved, and a solution mixture comprising 1.54 g of trichloroacetyl chloride and 3.8 ml of dry tetrahydrofuran was dropwise added thereto over a period of 10 minutes. Then, the mixture was reacted at room temperature for 3 hours. After completion of the reaction, precipitated crystals were collected by filtration and washed with tetrahydrofuran to obtain 2.2 g of N-(2-amino-5-trifluoromethyl-3-pyridyl)trichloroacetamide having a melting point of from 210° to 223° C.

(2) 2.20 g of N-(2-amino-5-trifluoromethyl-3-pyridyl)trichloroacetamide obtained in the above step (1) was dissolved in 45 ml of dry tetrahydrofuran, and a solvent mixture comprising 2.15 g of trifluoroacetic anhydride and 3 ml of dry tetrahydrofuran was dropwise added thereto under cooing with ice. After the dropwise addition, the mixture was reacted at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained crystals were washed with ethyl ether to obtain 1.20 g of the desired product (Compound No. 30) having a melting point of from 166° to 168° C.

PREPARATION EXAMPLE 4

Preparation of N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclohexanecarboxamide (Compound No. 47)

(1) 20.3 g of ethanesulfonamide and 26.0 g of 2-chloro-5-trifluoromethylpyridine were dissolved in 220 ml of dimethylsulfoxide, and 47.4 g of anhydrous potassium carbonate was further added thereto. This solution mixture was heated to 130° C. and reacted for 5 hours. After completion of the reaction, the reaction product was poured into 1 l of water. Undissolved materials in water were extracted with ethyl ether and removed. Then, the aqueous layer was adjusted to pH4 with concentrated hydrochloric acid, and precipitated crystals were collected by filtration and dried to obtain 26.2 g of N-(5-trifluoromethyl-2-pyridyl)ethanesulfonamide having a melting point of from 164° to 165° C.

(2) 45 g of N-(5-trifluoromethyl-2-pyridyl)ethanesulfonamide was dissolved in 112.5 ml of acetic acid. While heating it to a temperature of from 100° to 105° C., 26 g of fuming nitric acid (94%) was dropwise added, and the mixture was reacted for further 6 hours. The reaction product was left to cool to 80° C., and then poured into 2 l of ice water. Precipitated crystals were collected by filtration, washed with water and dried to obtain 47.8 g of N-(3-nitro-5-trifluoromethyl-2-pyridyl)ethanesulfonamide.

(3) 3.0 g of N-(3-nitro-5-trifluoromethyl-2-pyridyl)ethanesulfonamide was suspended in a solvent mixture comprising 30 ml of water and 30 ml of acetic acid, and 2.2 g of reduced iron was added thereto. Then, the mixture was heated to 50° C. and reacted for one hour. After completion of the reaction, the reaction product was cooled to room temperature, and excess iron was separated by filtration. The filtrate was extracted with ethyl acetate. The extract layer was washed with water and dried. Ethyl acetate was distilled off under reduced pressure to obtain 2.5 g of N-(3-amino-5-trifluoromethylethyl-2-pyridyl)ethanesulfonamide.

An alternative process will be described. To a solution prepared by dissolving 34.9 g of sodium hydrosulfite in 400 ml of water, a solution prepared by dissolving 5.0 g of N-(3-nitro-5-trifluoromethyl-2-pyridyl)ethanesulfonamide in 80 ml of tetrahydrofuran, was dropwise added at room temperature. After completion of the dropwise addition, the mixture was reacted for further 3 hours. After completion of the reaction, sodium chloride was added until the tetrahydrofuran layer was separated. The separated tetrahydrofuran layer was dried, and tetrahydrofuran was distilled off under reduced pressure to obtain 4.2 g of N-(3-amino-5-trifluoromethyl-2-pyridyl)ethanesulfonamide.

(4) 2.36 g of N-(3-amino-5-trifluoromethyl-2-pyridyl)ethanesulfonamide was dissolved in 24 ml of dry tetrahydrofuran, and 1.54 g of cyclohexanecarbonyl chloride was dropwise added thereto under cooing with ice. After the dropwise addition, the mixture was stirred for one hour and further reacted at room temperature overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, the obtained crystals were washed with ethyl ether to obtain 2.94 g of the desired product having a melting point of from 153° to 155° C.

An alternative process will be described. In 20 ml of methylene chloride, 0.5 g of 4-diemthylaminopyridine was dissolved, and 0.78 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added and dissolved. Then, 1 g of N-(3-amino-5-trifluoromethyl-2-pyridyl)ethanesulfonamide was added thereto, and 30 minutes later, 0.52 g of cyclohexanecarboxylic acid was added thereto, and stirring was conducted for 10 hours. After completion of the reaction, 40 ml of methylene chloride was added to the reaction product, and the reaction product was washed with 10% hydrochloric acid and then washed with an aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. From the extract layer, solvent was distilled off and the obtained residue was purified by silica gel column chromatography to obtain 0.88 g of the desired product.

PREPARATION EXAMPLE 5

Preparation of sodium salt of N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclohexanecarboxamide (Compound No. 251)

To 10 ml of an ethanol solution containing 1.00 g of N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclohexanecarboxamide, 2.75 g of a 1N-sodium hydroxide aqueous solution was added under stirring at 40° C., and the mixture was stirred for one hour. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained crystals were washed with ethyl ether to obtain 1.02 g of the desired product which decomposed at 299° C.

Trifluoromethylpyridine compounds of the above formula (VIII) are listed in Table 1.

                  TABLE 1                                                          ______________________________________                                          ##STR12##                   (VIII)                                            Intermediate                      Melting point                                No.      Q      Y.sup.5           (°C.)                                 ______________________________________                                         1        H      SO.sub.2 CH.sub.3 189˜191                                2        H      SO.sub.2 C.sub.2 H.sub.5                                                                         164˜165                                3        H      SO.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                              157˜159                                4        H      SO.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                     148˜150                                5        H                                                                                      ##STR13##        181˜184                                6        H                                                                                      ##STR14##                                                     7        H      SO.sub.2 CH.sub.2 CHCH.sub.2                                   8        H                                                                                      ##STR15##                                                     9        H      SO.sub.2 CH.sub.2 C(CH.sub.3)CH.sub.2                          10       H      SO.sub.2 CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.3                  11       H      SO.sub.2 CF.sub.3 215˜218                                12       H                                                                                      ##STR16##                                                     13       H                                                                                      ##STR17##                                                     14       H                                                                                      ##STR18##                                                     15       H      SO.sub.2 C.sub.3 H.sub.17 (n)                                  16       H      SO.sub.2 C.sub.18 H.sub.37 (n)                                 17       H      SO.sub.2 CF.sub.2 CF.sub.3                                     18       NO.sub.2                                                                              SO.sub.2 CH.sub.3 138˜139                                19       NO.sub.2                                                                              SO.sub.2 CH.sub.2 CH.sub.3                                                                       160˜163                                20       NO.sub.2                                                                               ##STR19##        138˜140                                21       NO.sub.2                                                                              SO.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                              109˜112                                22       NO.sub.2                                                                              SO.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                     76˜78                                  23       NO.sub.2                                                                               ##STR20##        138˜140                                24       NO.sub.2                                                                               ##STR21##        145˜146                                25       NO.sub.2                                                                              NHSO.sub.2 CH.sub.3                                                                              175˜182                                26       NO.sub.2                                                                               ##STR22##                                                     27       NO.sub.2                                                                               ##STR23##                                                     28       NO.sub.2                                                                               ##STR24##                                                     29       NO.sub.2                                                                               ##STR25##        51˜56                                  30       NO.sub.2                                                                               ##STR26##        156˜158                                31       NO.sub.2                                                                               ##STR27##                                                     32       NO.sub.2                                                                               ##STR28##                                                     33       NO.sub.2                                                                               ##STR29##                                                     34       NO.sub.2                                                                               ##STR30##        130˜132                                35       NO.sub.2                                                                               ##STR31##                                                     36       NO.sub.2                                                                               ##STR32##                                                     37       NO.sub.2                                                                               ##STR33##        192˜194                                38       NO.sub.2                                                                               ##STR34##                                                     39       NO.sub.2                                                                               ##STR35##                                                     40       NO.sub.2                                                                               ##STR36##                                                     41       NO.sub.2                                                                               ##STR37##                                                     42       NO.sub.2                                                                               ##STR38##                                                     43       NO.sub.2                                                                               ##STR39##                                                     44       NO.sub.2                                                                               ##STR40##                                                     45       NO.sub.2                                                                               ##STR41##                                                     46       NO.sub.2                                                                               ##STR42##                                                     47       NO.sub.2                                                                               ##STR43##                                                     48       NO.sub.2                                                                               ##STR44##        148˜149                                49       NO.sub.2                                                                               ##STR45##        132                                          50       NO.sub.2                                                                              SO.sub.2 CF.sub.3 126˜127                                51       NO.sub.2                                                                              SO.sub.3 CH.sub.3 93˜94                                  52       NO.sub.2                                                                              SO.sub.3 C.sub.2 H.sub.5                                                                         120˜121                                53       NO.sub.2                                                                               ##STR46##        104˜105                                54       NO.sub.2                                                                               ##STR47##                                                     55       NH.sub.2                                                                              SO.sub.2 CH.sub.3 128˜130                                56       NH.sub.2                                                                              SO.sub.2 CH.sub.2 CH.sub.3                                                                       118˜120                                57       NH.sub.2                                                                               ##STR48##        155˜157                                58       NH.sub.2                                                                              SO.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                              82˜84                                  59       NH.sub.2                                                                              SO.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                     102˜103                                60       NH.sub.2                                                                               ##STR49##        200˜204                                61       NH.sub.2                                                                               ##STR50##        170˜175                                62       NH.sub.2                                                                              NHSO.sub.2 CH.sub.3                                                                              128˜133                                63       NH.sub.2                                                                               ##STR51##                                                     64       NH.sub.2                                                                               ##STR52##                                                     65       NH.sub.2                                                                               ##STR53##                                                     66       NH.sub.2                                                                               ##STR54##        136˜139                                67       NH.sub.2                                                                               ##STR55##        164˜168                                68       NH.sub.2                                                                               ##STR56##                                                     69       NH.sub.2                                                                               ##STR57##                                                     70       NH.sub.2                                                                               ##STR58##                                                     71       NH.sub.2                                                                               ##STR59##        171˜174                                72       NH.sub.2                                                                               ##STR60##                                                     73       NH.sub.2                                                                               ##STR61##                                                     74       NH.sub.2                                                                               ##STR62##        168˜173                                75       NH.sub.2                                                                               ##STR63##                                                     76       NH.sub.2                                                                               ##STR64##                                                     77       NH.sub.2                                                                               ##STR65##                                                     78       NH.sub.2                                                                               ##STR66##                                                     79       NH.sub.2                                                                               ##STR67##                                                     80       NH.sub.2                                                                               ##STR68##                                                     81       NH.sub.2                                                                               ##STR69##                                                     82       NH.sub.2                                                                               ##STR70##                                                     83       NH.sub.2                                                                               ##STR71##                                                     84       NH.sub.2                                                                               ##STR72##                                                     85       NH.sub.2                                                                               ##STR73##        165˜167                                86       NH.sub.2                                                                               ##STR74##        134˜136                                87       NH.sub.2                                                                              SO.sub.2 CF.sub.3 122˜124                                88       NH.sub.2                                                                              SO.sub.3 CH.sub.3  97˜100                                89       NH.sub.2                                                                              SO.sub.3 C.sub.2 H.sub.5                                                                         131˜132                                90       NH.sub.2                                                                               ##STR75##        223˜227                                91       NH.sub.2                                                                               ##STR76##                                                     ______________________________________                                    

Compounds of the above formula (II) which are not included in the compounds of the above formula (VIII) are listed in Table 2.

                  TABLE 2                                                          ______________________________________                                          ##STR77##                    (II)                                             Intermediate                 Melting point                                     No.       Y                  (°C.)                                      ______________________________________                                         100                                                                                       ##STR78##         207˜210                                     101       NHCOOCH.sub.2 CH.sub.3                                                                            187˜192                                     102       COOCH.sub.2 CH.sub.3                                                                              289˜292                                     103       NHCOCH.sub.3                                                         104                                                                                       ##STR79##                                                           105                                                                                       ##STR80##                                                           106       CH.sub.3                                                             107       CH.sub.2 CH.sub.3                                                    108       COCH.sub.3                                                           109       COCH.sub.2 CHCH.sub.2                                                110                                                                                       ##STR81##                                                           111                                                                                       ##STR82##                                                           112                                                                                       ##STR83##                                                           113                                                                                       ##STR84##                                                           114                                                                                       ##STR85##                                                           115                                                                                       ##STR86##                                                           116       COCOCH.sub.3                                                         117                                                                                       ##STR87##                                                           ______________________________________                                    

Compounds of the above formula (III) are listed in Table 3.

                  TABLE 3                                                          ______________________________________                                          ##STR88##                    (III)                                            Intermediate No.                                                                          X               Melting point (°C.)                          ______________________________________                                         118        COCHCl.sub.2    170˜171                                       119        COCCl.sub.3     141˜143                                       120        COOCH.sub.2 CH.sub.3                                                                           151˜154                                       121                                                                                        ##STR89##      156˜158                                       122        COCOCH.sub.3                                                        123                                                                                        ##STR90##                                                          ______________________________________                                         124        CONHCOCH.sub.3                                                      125                                                                                        ##STR91##                                                          126                                                                                        ##STR92##      248˜251                                       ______________________________________                                    

Compounds of the above formula (IV) which are not included in the compounds of the above formula (VIII) are listed in Table 4.

                  TABLE 4                                                          ______________________________________                                          ##STR93##                    (IV)                                             Intermediate No.                                                                          Y.sup.2         Melting point (°C.)                          ______________________________________                                         127                                                                                        ##STR94##      189˜195                                       128        NHCOOCH.sub.2 CH.sub.3                                                                         97˜99                                         129        NHCOCH.sub.3                                                        130        CH.sub.3                                                            131        CH.sub.2 CH.sub.3                                                   ______________________________________                                    

Typical specific examples of the compound of the formula (I) of the present invention are listed in Table 5.

                                      TABLE 5                                      __________________________________________________________________________      ##STR95##                                      (I)                            Compound                                 Melting point                         No.    X                  Y              (°C.)                          __________________________________________________________________________     1      CO(CH.sub.2).sub.2 CH.sub.3                                                                       SO.sub.2 CH.sub.3                                                                             113˜114                         2      CO(CH.sub.2).sub.3 CH.sub.3                                                                       SO.sub.2 CH.sub.3                                                                             119˜121                         3      CO(CH.sub.2).sub.4 CH.sub.3                                                                       SO.sub.2 CH.sub.3                                                                             119˜122                         4      CO(CH.sub.2).sub.7 CH.sub.3                                                                       SO.sub.2 CH.sub.3                                                                              99˜101                         5      CO(CH.sub.2).sub.10 CH.sub.3                                                                      SO.sub.2 CH.sub.3                                                                              94˜97                          6      CO(CH.sub.2).sub.14 CH.sub.3                                                                      SO.sub.2 CH.sub.3                                                                              99˜103                         7      COCH.sub.2 C(CH.sub.3).sub.3                                                                      SO.sub.2 CH.sub.3                                                                             150˜151                                 ##STR96##         SO.sub.2 CH.sub.3                                                                             110˜116                         9      COCHCH.sub.2       SO.sub.2 CH.sub.3                                                                             174˜176                         10                                                                                     ##STR97##         SO.sub.2 CH.sub.3                                                                             211˜213                         11     COCF.sub.2 Cl      SO.sub.2 CH.sub.3                                                                             199˜201                         12     COCF.sub.3         SO.sub.2 CH.sub.3                                                                             154˜157                         13     COCF.sub.2 CF.sub.3                                                                               SO.sub.2 CH.sub.3                                                                             186˜189                         14     COCF.sub.2 CF.sub.2 CF.sub.3                                                                      SO.sub.2 CH.sub.3                                                                             170˜173                         15     COOC.sub.2 H.sub.5 SO.sub.2 CH.sub.3                                                                             180˜182                         16     COO(CH.sub.2).sub.2 CH.sub.3                                                                      SO.sub.2 CH.sub.3                                                                             173˜176                         17     COO(CH.sub.2).sub.3 CH.sub.3                                                                      SO.sub.2 CH.sub.3                                                                             127˜129                         18     CSNHCOOC.sub.2 H.sub.5                                                                            SO.sub.2 CH.sub.3                                                                             More than 300                         19     COCF.sub.2 CF.sub.3                                                                               SO.sub.2 C.sub.2 H.sub.5                                                                      168˜170                         20     COCF.sub.2 Cl      SO.sub.2 C.sub.2 H.sub.5                                                                      171˜174                         21     CSNHCOOC.sub.2 H.sub.5                                                                            SO.sub.2 C.sub.2 H.sub.5                                                                      More than 300                         22     COCF.sub.2 CF.sub.3                                                                               SO.sub.2 C.sub.3 H.sub.7 (n)                                                                  129˜133                         23     COCF.sub.2 CF.sub.3                                                                               SO.sub.2 C.sub.8 H.sub.17 (n)                                                                 109˜112                         24     COCF.sub.3                                                                                         ##STR98##     160˜163                         25     CSNHCOOC.sub.2 H.sub.5                                                                             ##STR99##     195˜200                         26     CO(CH.sub.2).sub.2 OC.sub.2 H.sub.5                                                               CO(CH.sub.2).sub.2 OC.sub.2 H.sub.5                                                            75˜76                          27     COCF.sub.3         COCHCl.sub.2   117˜119                         28     COCHCl.sub.2       COCHCl.sub.2   158˜159                         29     COCHCl.sub.2       COCF.sub.3     117˜178                         30     COCCl.sub.3        COCF.sub.3     166˜168                         31                                                                                     ##STR100##        SO.sub.2 C.sub.2 H.sub.5                                                                      135˜137                         32                                                                                     ##STR101##        COCF.sub.2 CF.sub.3                                                                           228˜230                         33                                                                                     ##STR102##        SO.sub.2 C.sub.2 H.sub.5                                                                      130˜134                         34                                                                                     ##STR103##        SO.sub.2 CH.sub.3                                                                             218˜222                         35                                                                                     ##STR104##        SO.sub.2 CH.sub.3                                                                             219˜224                         36                                                                                     ##STR105##        SO.sub.2 C.sub.2 H.sub.5                             37     COOC.sub.2 H.sub.5 COOC.sub.2 H.sub.5                                                                            112˜114                         38                                                                                     ##STR106##        COOC.sub.2 H.sub.5                                                                            134˜137                         39     COCF.sub.2 CF.sub.3                                                                                ##STR107##    214˜217                         40     COCF.sub.2 CF.sub.3                                                                               NHSO.sub.2 CH.sub.3                                                                           136˜138                         41     COCF.sub.2 CF.sub.3                                                                               CH.sub.3        89˜90                          42                                                                                     ##STR108##                                                                                        ##STR109##                                          43                                                                                     ##STR110##        SO.sub.2 CH.sub.3                                                                             189˜192                         44                                                                                     ##STR111##        SO.sub.2 CH.sub.3                                                                             217˜220                         45                                                                                     ##STR112##        SO.sub.2 CH.sub.3                                                                             153˜155                         46     CO(CH.sub.2).sub.3 Cl                                                                             SO.sub.2 CH.sub.3                                                                              79˜85                          47                                                                                     ##STR113##        SO.sub.2 CH.sub.2 CH.sub.3                                                                    153˜155                         48                                                                                     ##STR114##        SO.sub.2 CH.sub.2 CH.sub.3                                                                    204˜210                         49     COCHCH.sub.2       SO.sub.2 CH.sub.2 CH.sub.3                                                                    148˜151                         50     COCCl.sub.3                                                                                        ##STR115##    178˜180                         51     COCF.sub.2 CF.sub.3                                                                                ##STR116##    161˜163                         52     COCF.sub.2 CF.sub.3                                                                               SO.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                  146˜149                         53                                                                                     ##STR117##        SO.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                  152˜154                         54     CSNHCOOC.sub.2 H.sub.5                                                                            CH.sub.3       191˜193                         55     COCHCHCH.sub.3     SO.sub.2 CH.sub.3                                                                             158˜161                         56                                                                                     ##STR118##        SO.sub.2 C.sub.2 H.sub.5                                                                      234˜237                         57                                                                                     ##STR119##        SO.sub.2 CH.sub.3                                                                             210˜214                         58                                                                                     ##STR120##        SO.sub.2 CH.sub.3                                                                             220˜222                         59     COCF.sub.2 CF.sub.2 H                                                                             SO.sub.2 C.sub.2 H.sub.5                             60                                                                                     ##STR121##        SO.sub.2 CH.sub.3                                                                             163˜166                         61                                                                                     ##STR122##        SO.sub.2 CH.sub.3                                                                             172˜174                         62                                                                                     ##STR123##        SO.sub.2 CH.sub.3                                                                             147˜148                         63     COCH.sub.2 OCOCH.sub.3                                                                            SO.sub.2 CH.sub.3                                                                             155˜156                         64                                                                                     ##STR124##        SO.sub.2 CH.sub.3                                                                             163˜165                         65     COCH(C.sub.2 H.sub.5)(CH.sub.2).sub.3 CH.sub.3                                                    SO.sub. 2 CH.sub.3                                                                            141˜144                         66                                                                                     ##STR125##        SO.sub.2 CH.sub.3                                                                             128˜130                         67                                                                                     ##STR126##        SO.sub.2 CH.sub.3                                                                             126˜130                         68                                                                                     ##STR127##        SO.sub.2 CH.sub.3                                                                             143˜145                         69                                                                                     ##STR128##        SO.sub.2 CH.sub.3                                                                             176˜179                         70     COCHC(CH.sub.3).sub.2                                                                             SO.sub.2 CH.sub.3                                                                             187˜188                         71                                                                                     ##STR129##        SO.sub.2 CH.sub.3                                                                             215˜218                         72                                                                                     ##STR130##        SO.sub.2 CH.sub.3                                                                             227˜229                         73     COCHCHCHCHCH.sub.3 SO.sub.2 CH.sub.3                                                                             ≧300                           74     CO(CH.sub.2).sub.2 CHCH.sub.2                                                                     SO.sub.2 CH.sub.3                                                                              91˜93                          75                                                                                     ##STR131##        SO.sub.2 CH.sub.3                                                                             209˜210                         76                                                                                     ##STR132##        SO.sub.2 CH.sub.3                                                                             245˜249                         77                                                                                     ##STR133##        SO.sub.2 CH.sub.3                                                                             229˜231                         78                                                                                     ##STR134##        SO.sub.2 CH.sub.3                                                                             187˜189                         79                                                                                     ##STR135##        SO.sub.2 CH.sub.3                                                                             198˜201                         80                                                                                     ##STR136##        SO.sub.2 CH.sub.3                                                                             230˜233                         81                                                                                     ##STR137##        SO.sub.2 CH.sub.3                                                                             211˜215                         82                                                                                     ##STR138##        SO.sub.2 CH.sub.3                                                                             206˜210                         83                                                                                     ##STR139##        SO.sub.2 CH.sub.3                                                                             207˜210                         84                                                                                     ##STR140##        SO.sub.2 CH.sub.3                                                                             202˜205                         85                                                                                     ##STR141##        SO.sub.2 CH.sub.3                                                                             227˜231                         86                                                                                     ##STR142##        SO.sub.2 CH.sub.3                                                                             250˜252                         87                                                                                     ##STR143##        SO.sub.2 CH.sub.3                                                                             194˜197                         88                                                                                     ##STR144##        SO.sub.2 CH.sub.3                                                                             229˜233                         89     COCCl.sub.2 CH.sub.3                                                                              SO.sub.2 CH.sub.3                                                                             212˜214                         90                                                                                     ##STR145##        SO.sub.2 CH.sub.3                                                                             231˜234                         91                                                                                     ##STR146##        SO.sub.2 CF.sub.3                                                                             175˜178                         92                                                                                     ##STR147##        SO.sub.2 CF.sub.3                                                                             209˜210                         93     COCHCHCH.sub.3     SO.sub.2 C.sub.2 H.sub.5                                                                      158˜160                         94                                                                                     ##STR148##        SO.sub.2 C.sub.2 H.sub.5                                                                      157˜161                         95                                                                                     ##STR149##        SO.sub.2 C.sub.2 H.sub.5                                                                      147˜148                         96                                                                                     ##STR150##        SO.sub.2 C.sub.2 H.sub.5                                                                      163˜165                         97                                                                                     ##STR151##        SO.sub.2 C.sub.2 H.sub.5                                                                      163˜166                         98                                                                                     ##STR152##        SO.sub.2 C.sub.2 H.sub.5                                                                      204˜208                         99                                                                                     ##STR153##        SO.sub.2 C.sub.2 H.sub.5                                                                      215˜218                         100                                                                                    ##STR154##        SO.sub.2 C.sub.2 H.sub.5                                                                      233˜237                         101                                                                                    ##STR155##        SO.sub.2 C.sub.2 H.sub.5                                                                      208˜209                         102                                                                                    ##STR156##        SO.sub.2 C.sub.2 H.sub.5                                                                      188˜190                         103                                                                                    ##STR157##        SO.sub. 2 C.sub.3 H.sub.7 (iso)                                                               152˜154                         104                                                                                    ##STR158##        SO.sub.2 C.sub.3 H.sub.7 (iso)                                                                216˜217                         105                                                                                    ##STR159##        SO.sub.2 C.sub.3 H.sub.7 (iso)                                                                227˜230                         106    COOC.sub.3 H.sub.7 (n)                                                                            SO.sub.2 C.sub.3 H.sub.7 (iso)                                                                161˜163                         107                                                                                    ##STR160##        SO.sub.2 C.sub.4 H.sub.9 (n)                                                                  138˜139                         108    COCF.sub.2 Cl      SO.sub.2 C.sub.4 H.sub.9 (n)                                                                  156                                   109                                                                                    ##STR161##                                                                                        ##STR162##    202˜205                         110    CO(CH.sub.2).sub.4 CH.sub.3                                                                       SO.sub.2 N(CH.sub.3).sub.2                                                                     97                                   111                                                                                    ##STR163##        SO.sub.2 N(CH.sub.3).sub.2                                                                    168˜169                         112    COCF.sub.2 CF.sub.3                                                                               SO.sub.2 N(CH.sub.3).sub.2                                                                    157˜159                         113                                                                                    ##STR164##        SO.sub.2 N(CH.sub.3).sub.2                                                                    189˜191                         114    COOC.sub.3 H.sub.7 (n)                                                                            SO.sub.2 N(CH.sub.3).sub.2                                                                    174˜176                         115                                                                                    ##STR165##        SO.sub.2 OCH.sub.3                                                                            147˜148                         116                                                                                    ##STR166##        SO.sub.2 OCH.sub.3                                                                            163˜164                         117                                                                                    ##STR167##        SO.sub.2 OC.sub.2 H.sub.5                                                                     140˜141                         118                                                                                    ##STR168##        SO.sub.2 OC.sub.2 H.sub.5                                                                     160˜162                         119                                                                                    ##STR169##        SO.sub.2 C.sub.2 H.sub.5                                                                      137˜139                         120                                                                                    ##STR170##        SO.sub.2 CH.sub.3                                                                             202˜203                         121                                                                                    ##STR171##        SO.sub.2 CH.sub.3                                                                             145˜147                         122                                                                                    ##STR172##        SO.sub.2 CH.sub.3                                                                             221˜224                         123                                                                                    ##STR173##        SO.sub.2 CH.sub.3                                                                             184˜185                         124    CO(CH.sub.2).sub.5 CH.sub.3                                                                       SO.sub.2 CH.sub.3                                                                              94˜96                          125    CO(CH.sub.2).sub.6 CH.sub.3                                                                       SO.sub.2 CH.sub.3                                                                              94˜96                          126                                                                                    ##STR174##                                                                                        ##STR175##    178˜180                         127                                                                                    ##STR176##                                                                                        ##STR177##    226˜228                         128                                                                                    ##STR178##        SO.sub.2 CH.sub.3                                    129                                                                                    ##STR179##        SO.sub.2 CH.sub.3                                    130                                                                                    ##STR180##        SO.sub.2 CH.sub.3                                    131                                                                                    ##STR181##        SO.sub.2 CH.sub.3                                    132                                                                                    ##STR182##        SO.sub.2 CH.sub.3                                    133                                                                                    ##STR183##                                                                                        ##STR184##                                          134                                                                                    ##STR185##                                                                                        ##STR186##                                          135                                                                                    ##STR187##                                                                                        ##STR188##                                          136                                                                                    ##STR189##        SO.sub.2 C.sub.2 H.sub.5                             137                                                                                    ##STR190##                                                                                        ##STR191##                                          138                                                                                    ##STR192##                                                                                        ##STR193##                                          139                                                                                    ##STR194##                                                                                        ##STR195##    138˜140                         140                                                                                    ##STR196##                                                                                        ##STR197##    190˜192                         141                                                                                    ##STR198##                                                                                        ##STR199##                                          142                                                                                    ##STR200##        SO.sub.2 C.sub.2 H.sub.5                                                                      210˜211                         143                                                                                    ##STR201##        SO.sub.2 C.sub.2 H.sub.5                             144                                                                                    ##STR202##        SO.sub.2 C.sub.2 H.sub.5                             145                                                                                    ##STR203##                                                                                        ##STR204##                                          146                                                                                    ##STR205##        SO.sub.2 C.sub.2 H.sub.5                             147                                                                                    ##STR206##        SO.sub.2 C.sub.2 H.sub.5                             148                                                                                    ##STR207##        SO.sub.2 C.sub.2 H.sub.5                             149                                                                                    ##STR208##        SO.sub.2 C.sub.2 H.sub.5                             150                                                                                    ##STR209##                                                                                        ##STR210##                                          151                                                                                    ##STR211##                                                                                        ##STR212##                                          152                                                                                    ##STR213##        SO.sub.2 C.sub.2 H.sub.5                             153                                                                                    ##STR214##                                                                                        ##STR215##                                          154                                                                                    ##STR216##                                                                                        ##STR217##    166˜167                         155                                                                                    ##STR218##                                                                                        ##STR219##    144˜146                         156                                                                                    ##STR220##                                                                                        ##STR221##                                          157                                                                                    ##STR222##        SO.sub.2 C.sub.2 H.sub.5                             158                                                                                    ##STR223##        SO.sub.2 C.sub.2 H.sub.5                             159                                                                                    ##STR224##                                                                                        ##STR225##                                          160                                                                                    ##STR226##                                                                                        ##STR227##                                          161                                                                                    ##STR228##        SO.sub.2 C.sub.2 H.sub.5                             162                                                                                    ##STR229##                                                                                        ##STR230##    133˜135                         163                                                                                    ##STR231##        SO.sub.2 C.sub.2 H.sub.5                             164                                                                                    ##STR232##        SO.sub.2 C.sub.2 H.sub.5                             165                                                                                    ##STR233##        SO.sub.2 C.sub.2 H.sub.5                             166                                                                                    ##STR234##        SO.sub.2 C.sub.2 H.sub.5                             167                                                                                    ##STR235##                                                                                        ##STR236##                                          168                                                                                    ##STR237##        SO.sub.2 C.sub.2 H.sub.5                             169                                                                                    ##STR238##        SO.sub.2 C.sub.2 H.sub.5                             170                                                                                    ##STR239##        SO.sub.2 C.sub.2 H.sub.5                             171                                                                                    ##STR240##         SO.sub.2 C.sub.2 H.sub.5                            172                                                                                    ##STR241##        SO.sub.2 C.sub.2 H.sub.5                             173                                                                                    ##STR242##        SO.sub.2 C.sub.2 H.sub.5                             174                                                                                    ##STR243##        SO.sub.2 C.sub.2 H.sub.5                             175                                                                                    ##STR244##        SO.sub.2 C.sub.2 H.sub.5                             176                                                                                    ##STR245##        SO.sub.2 C.sub. 2 H.sub.5                            177                                                                                    ##STR246##        SO.sub.2 C.sub.2 H.sub.5                             178                                                                                    ##STR247##        SO.sub.2 C.sub.2 H.sub.5                             179                                                                                    ##STR248##        SO.sub.2 C.sub.2 H.sub.5                             180                                                                                    ##STR249##        SO.sub.2 C.sub.2 H.sub.5                             181                                                                                    ##STR250##        SO.sub.2 C.sub.2 H.sub.5                             182                                                                                    ##STR251##        SO.sub.2 C.sub.2 H.sub.5                             183                                                                                    ##STR252##        SO.sub.2 C.sub.2 H.sub.5                             184                                                                                    ##STR253##                                                                                        ##STR254##                                          185                                                                                    ##STR255##        SO.sub.2 C.sub.2 H.sub.5                             186                                                                                    ##STR256##                                                                                        ##STR257##                                          187                                                                                    ##STR258##         SO.sub.2 C.sub.2 H.sub.5                            188                                                                                    ##STR259##        SO.sub.2 C.sub.2 H.sub.5                             189                                                                                    ##STR260##        SO.sub.2 C.sub.2 H.sub.5                             190                                                                                    ##STR261##        SO.sub.2 C.sub.2 H.sub.5                             191                                                                                    ##STR262##                                                                                        ##STR263##                                          192                                                                                    ##STR264##        SO.sub.2 C.sub.2 H.sub.5                             193                                                                                    ##STR265##        SO.sub.2 C.sub.2 H.sub.5                             194                                                                                    ##STR266##        SO.sub.2 C.sub.2 H.sub.5                             195                                                                                    ##STR267##        SO.sub.2 C.sub.2 H.sub.5                             196                                                                                    ##STR268##        SO.sub.2 C.sub.2 H.sub.5                             197                                                                                    ##STR269##        SO.sub.2 C.sub.2 H.sub.5                             198                                                                                    ##STR270##        SO.sub.2 C.sub.2 H.sub.5                             199                                                                                    ##STR271##        SO.sub.2 C.sub.2 H.sub.5                             200                                                                                    ##STR272##        SO.sub.2 C.sub.2 H.sub.5                             201                                                                                    ##STR273##        SO.sub.2 C.sub.2 H.sub.5                             202                                                                                    ##STR274##        SO.sub.2 C.sub.2 H.sub.5                             203                                                                                    ##STR275##                                                                                        ##STR276##                                          204                                                                                    ##STR277##        SO.sub.2 C.sub.2 H.sub.5                             205                                                                                    ##STR278##        SO.sub.2 C.sub.2 H.sub.5                             206                                                                                    ##STR279##        SO.sub.2 C.sub.2 H.sub.5                             207                                                                                    ##STR280##        SO.sub.2 C.sub.2 H.sub.5                                                                      265˜266                         208                                                                                    ##STR281##                                                                                        ##STR282##                                          209                                                                                    ##STR283##        SO.sub.2 C.sub.2 H.sub.5                             210                                                                                    ##STR284##        SO.sub.2 C.sub.2 H.sub.5                             211                                                                                    ##STR285##        SO.sub.2 C.sub.2 H.sub.5                             212                                                                                    ##STR286##                                                                                        ##STR287##                                          213                                                                                    ##STR288##        SO.sub.2 C.sub.2 H.sub.5                             214                                                                                    ##STR289##        SO.sub.2 C.sub.2 H.sub.5                                                                      248˜249                         215                                                                                    ##STR290##        SO.sub.2 C.sub.2 H.sub.5                             216                                                                                    ##STR291##        SO.sub.2 C.sub.2 H.sub.5                             217                                                                                    ##STR292##        SO.sub.2 C.sub.2 H.sub.5                                                                      219˜221                         218                                                                                    ##STR293##        SO.sub.2 C.sub.2 H.sub.5                                                                      241˜242                         219                                                                                    ##STR294##                                                                                        ##STR295##                                          220                                                                                    ##STR296##        SO.sub.2 C.sub.2 H.sub.5                             221                                                                                    ##STR297##                                                                                        ##STR298##                                          222                                                                                    ##STR299##        SO.sub.2 C.sub.2 H.sub.5                             223                                                                                    ##STR300##        SO.sub.2 C.sub.2 H.sub.5                             224                                                                                    ##STR301##        SO.sub.2 C.sub.2 H.sub.5                             225                                                                                    ##STR302##        SO.sub.2 C.sub.2 H.sub.5                             226                                                                                    ##STR303##        SO.sub.2 C.sub.2 H.sub.5                             227                                                                                    ##STR304##        SO.sub.2 C.sub.2 H.sub.5                             228                                                                                    ##STR305##        SO.sub.2 C.sub.2 H.sub.5                             229                                                                                    ##STR306##        SO.sub.2 C.sub.2 H.sub.5                             230                                                                                    ##STR307##        SO.sub.2 C.sub.2 H.sub.5                             231                                                                                    ##STR308##        SO.sub.2 C.sub.2 H.sub.5                             232                                                                                    ##STR309##        SO.sub.2 C.sub.2 H.sub.5                             233                                                                                    ##STR310##        SO.sub.2 C.sub.2 H.sub.5                             234                                                                                    ##STR311##        SO.sub.2 C.sub.2 H.sub.5                             235                                                                                    ##STR312##        SO.sub.2 C.sub.2 H.sub.5                             236                                                                                    ##STR313##        SO.sub.2 C.sub.2 H.sub.5                             237                                                                                    ##STR314##        SO.sub.2 C.sub.2 H.sub.5                             238                                                                                    ##STR315##        SO.sub.2 C.sub.2 H.sub.5                             239                                                                                    ##STR316##        SO.sub.2 C.sub.2 H.sub.5                             240                                                                                    ##STR317##        SO.sub.2 C.sub.2 H.sub.5                             241                                                                                    ##STR318##        SO.sub.2 C.sub.2 H.sub.5                             242                                                                                    ##STR319##        SO.sub.2 C.sub.2 H.sub.5                             243                                                                                    ##STR320##        SO.sub.2 C.sub.2 H.sub.5                             244                                                                                    ##STR321##        SO.sub.2 C.sub.2 H.sub.5                             245                                                                                    ##STR322##        SO.sub.2 C.sub.2 H.sub.5                             246                                                                                    ##STR323##                                                                                        ##STR324##                                          247                                                                                    ##STR325##        SO.sub.2 C.sub.2 H.sub.5                             248                                                                                    ##STR326##                                                                                        ##STR327##                                          249                                                                                    ##STR328##        SO.sub.2 C.sub.3 H.sub.7 (n)                         __________________________________________________________________________     Compound                             Type of                                                                             Melting point                        No.   X                Y             salt (°C.)                         __________________________________________________________________________     250                                                                                   ##STR329##      SO.sub.2 C.sub.3 H.sub.7 (n)                            251                                                                                   ##STR330##      SO.sub.2 C.sub.2 H.sub.5                                                                     Na salt                                                                             299 (decomposed)                     252                                                                                   ##STR331##      SO.sub.2 C.sub.2 H.sub.5                                                                     K salt                                                                              More than 300                        253                                                                                   ##STR332##      SO.sub.2 C.sub.3 H.sub.7 (iso)                                                               Na salt                                   254                                                                                   ##STR333##      SO.sub.2 CF.sub.3                                                                            Na salt                                   255                                                                                   ##STR334##                                                                                      ##STR335##   Na salt                                   256                                                                                   ##STR336##      SO.sub.2 C.sub.2 H.sub.5                                                                     Na salt                                   257                                                                                   ##STR337##      SO.sub.2 C.sub.2 H.sub.5                                                                     Na salt                                   258                                                                                   ##STR338##      SO.sub.2 C.sub.2 H.sub.5                                                                     Na salt                                   259                                                                                   ##STR339##      SO.sub.2 CH.sub.3                                                                            Na salt                                                                             More than 300                        260   COCF.sub.2 CF.sub.3                                                                             SO.sub.2 CH.sub.3                                                                            Na salt                                                                             More than 300                        261   COCF.sub.2 CF.sub.3                                                                             SO.sub.2 C.sub.2 H.sub.5                                                                     Na salt                                   262                                                                                   ##STR340##      SO.sub.2 C.sub.2 H.sub.5                                                                     Ca salt                                                                             245 (decomposed)                     __________________________________________________________________________

The compound of the formula (I) of the present invention is useful as an active ingredient for a phospholipase A₂ inhibitor, an anti-inflammatory agent or an anti-pancreatitis agent. Phospholipase A₂ can be detected in various tissues or cells in a body. It is said that in platelets or cells related to inflammatory symptoms, phospholipase A₂ is secreted or activated by various stimulations and contributes to the production of a platelet activating factor (PAF) or some arachidonic acid methabolites. The arachidonic acid methabolites have been found to be closely related to various diseases, for example, inflammatory symptoms such as rheumatoid arthritis, arthritis deformans, tenontitis, psoriasis and related dermatitis; nasal and bronchial airway troubles such as allergic rhinitis and allergic bronchial asthma; and immediate hypersensitive reactions such as allergic conjunctivitis. On the other hand, phospholipase A₂ secreted from pancreas is activated in the intestine and exhibits a digestive action, but once activated in the pancreas, it is believed to be one of the factors causing pancreatitis. The compound of the present invention inhibits phospholipase A₂ and thus is effective for the treatment of the above-mentioned diseases caused by phospholipase A.sub. 2 such as inflammatory symptoms, nasal and bronchial airway troubles, immediate hypersensitive reactions or pancreatitis. Thus, it is useful as an anti-inflammatory agent, an agent for treating bronchial asthma, an anti-allergy agent, an anti-pancreatitis agent, anti-nephritis agent, or anti-MOFC (Multiple Organ Failure).

In regard to the efficacy against pancreatitis, the compound of the present invention is expected to be more efficient by using in combination with other drugs, for example, a proteinase inhibitor, such as galexate mesilate, camostat mesilate, or nafamostat mesilate.

The compound of the present invention is particularly suitable for use as an anti-inflammatory agent and/or an anti-pancreatitis agent.

TEST EXAMPLE 1

Phospholipase A₂ inhibitory activity, method A

(1) Preparation of substrate

To 10 mg of egg yolk lecithin (manufactured by Wako Pure Chemical Industries Ltd.), 1 ml of glycerine, 2 ml of a 50 mM Tris-HCl buffer solution (pH7.5) [Tris(hydroxymethyl)aminomethane (manufactured by Nacalai Tesque K.K.) was adjusted to pH7.5 with hydrochloric acid], 0.5 ml of a 150 mM calcium chloride solution (calcium chloride was dissolved in a 50 mM Tris-HCl buffer solution) and 0.5 ml of a 0.05% Triton-X100 (manufactured by Nacalai Tesque K.K.) solution (Triton-X100 was dissolved in a 50 mM Tris-HCl buffer solution), were added and dispersed by an agate mortar or dispersed by an ultrasonic processor (Model W-225, manufactured by Heat System-Ultrasonics, Inc.) for 5 minutes (30 W) to obtain a substrate.

(2) Enzyme

Porcine pancreatic phospholipase A₂ [(161454.122416) manufactured by Boehringer Mannheim.Yamanouchi K.K.] was used.

(3) Measurement of phospholipase A₂ activity

To a 96 well microtitration plate (flat bottom, manufactured by Sumitomo Bakelite Medical Co., Ltd.), 40 μl of the substrate, 5 μl of a solution prepared by dissolving 10 mg of a test compound in 500 μl of dimethylsulfoxide, followed by an addition of 500 μl of a 50 mM Tris-HCl buffer solution, and 5 μl of an enzyme solution of 20 ng/ml (prepared by diluting the enzyme in a 50 mM Tris-HCl buffer solution), were added and reacted at 37° C. for 30 minutes. After termination of the reaction, the released free fatty acid was quantitatively analyzed in accordance with the ACS-ACOD (acyl CoA synthetase-acyl CoA oxidase) method [a kit of NEFA C test wako (manufactured by Wako Pure Chemical Industries, Ltd.) was used]. The quantitative analysis was made by means of Microplate ELISA Reader (Model 2550EIA Reader, manufactured by Bio-Rad Laboratories) at a wavelength of 540 nm. Separately, such experiments as mentioned above, were carried out at various concentrations (2 μg/ml, 1 μg/ml and 0.5 μg/ml) of phospholipase A₂ without a test compound. Then, the concentration of the free fatty acid versus the concentration of phospholipase A₂ was plotted.

From this standard curve, the apparent concentration of phospholipase A₂ in the case with a test compound, was read. Then, the percent inhibition of the enzyme was calculated by the following formula. The results are shown in Table 6. ##EQU1##

A: Apparent enzyme concentration when a test compound is added.

B: True enzyme concentration when a test compound is added.

                  TABLE 6                                                          ______________________________________                                                        % Inhibition of                                                 Compound No.   PLA.sub.2 (1,000 ppm)                                           ______________________________________                                         1              45                                                              2              55                                                              3              67                                                              4              74                                                              5              39                                                              8              81                                                              9              71                                                              10             60                                                              11             52                                                              12             89                                                              13             87                                                              14             54                                                              15             62                                                              16             43                                                              17             46                                                              18             64                                                              19             >90                                                             20             74                                                              21             62                                                              22             74                                                              23             37                                                              24             66                                                              26             35                                                              27             62                                                              28             71                                                              29             47                                                              30             87                                                              32             50                                                              38             35                                                              39             41                                                              41             89                                                              43             47                                                              44             43                                                              45             50                                                              46             47                                                              47             75                                                              48             48                                                              49             30                                                              50             78                                                              51             63                                                              52             49                                                              53             37                                                              54             37                                                              55             49                                                              57             57                                                              58             74                                                              ______________________________________                                    

TEST EXAMPLE 2

Phospholipase A₂ inhibitory activity, method B

(1) Preparation of substrate

To a solution prepared by dissolving 9.2 mg of L-α-dipalmitoylphosphatidylcholine (manufactured by Nichiyu Liposome K.K.) in 0.5 ml of chloroform, a solution prepared by dissolving 32 mg of sodium cholate (manufactured by Wako Pure Chemical Industries, Ltd.) in 0.5 ml of methanol, was added, followed by mixing. The solvent of the mixture was removed under a nitrogen stream, and then 2.5 ml of a 250 mM sodium chloride solution [prepared by dissolving sodium chloride in a 100 mM Tris-HCl buffer solution {tris(hydroxymethyl)aminomethane (manufactured by Nacalai Tesque K.K.) was adjusted to pH8.0 with hydrochloric acid}] was added thereto, and the mixture was dissolved under stirring to obtain a substrate.

(2) Enzyme

Porcine pancreatic phospholipase A₂ [(161454.122416) manufactured by Boehringer Mannheim.Yamanouchi K.K.] was used.

(3) Measurement of phospholipase A₂ activity

To a 96 well microtitration plate, 20 μl of a solution containing calcium chloride, bovine serum alubmin (manufactured by Sigma Chemical, Co.) and a Tris-HCl buffer solution (pH8.0) at concentrations of 25 mM, 4.5 mg/ml and 100 mM, respectively, 5 μl of a solution prepared by dissolving 10 mg of a test compound in 500 μl of diemthylsulfoxide, followed by an addition of 500 μl of a 200 mM Tris-HCl buffer solution, 5 μl of an enzyme solution (10 μg/ml) [prepared by dissolving the enzyme in a bovine serum alubmin solution (prepared by dissolving bovine serum alubmin in a 100 mM Tris-HCl buffer solution at a concentration of 1 mg/ml)] and 20 μl of the substrate, were added and reacted at 37° C. for 30 minutes. After termination of the reaction, the released free fatty acid was quantitatively analyzed in accordance with the ACS-ACOD (acyl CoA synthetase-acyl CoA oxidase) method [a kit of NEFA C test wako (manufactured by Wako Pure Chemical Industries, Ltd.) was used]. The quantitative analysis was made by means of Microplate ELISA Reader (Model 2550EIA Reader, manufactured by Bio-Rad Laboratories) at a wavelength of 540 nm. Separately, such experiments as mentioned above, were carried out at various concentrations (1 μg/ml, 0.75 μg/ml, 0.5 μg/mol and 0.25 μg/ml) of phospholipase A₂ without a test compound. Then, the concentration of the free fatty acid versus the concentration of phospholipase A₂ was plotted.

From this standard curve, the apparent concentration of phospholipase A₂ in the case with a test compound, was read. Then, the percent inhibition of the enzyme was calculated by the following formula. The results are shown in Table 7. ##EQU2##

A: Apparent enzyme concentration when a test compound is added.

B: True enzyme concentration when a test compound is added.

                  TABLE 7                                                          ______________________________________                                                        % inhibition of                                                 Compound No.   PLA.sub.2 (1,000 ppm)                                           ______________________________________                                          7             50                                                              10             51                                                              13             51                                                              18             49                                                              19             75                                                              43             49                                                              44             64                                                              45             41                                                              47             90                                                              53             100                                                             58             42                                                              60             41                                                              61             36                                                              62             53                                                              63             34                                                              64             61                                                              65             71                                                              66             52                                                              67             82                                                              68             81                                                              69             63                                                              70             40                                                              71             77                                                              72             73                                                              73             53                                                              74             33                                                              75             81                                                              76             61                                                              77             61                                                              78             51                                                              79             65                                                              80             73                                                              81             94                                                              82             38                                                              83             64                                                              84             56                                                              85             33                                                              86             93                                                              87             88                                                              88             83                                                              89             51                                                              90             79                                                              91             81                                                              92             75                                                              93             48                                                              94             63                                                              95             85                                                              97             88                                                              98             65                                                              99             86                                                              100            83                                                              103            86                                                              104            61                                                              106            78                                                              108            61                                                              109            67                                                              110            58                                                              111            41                                                              112            79                                                              113            35                                                              114            53                                                              115            52                                                              116            69                                                              117            65                                                              118            84                                                              121            90                                                              122            56                                                              123            86                                                              124            78                                                              125            86                                                              126            84                                                              127            89                                                              251            85                                                              259            61                                                              260            53                                                              ______________________________________                                    

TEST EXAMPLE 3

Inhibitory activity on increased vascular permeability induced by acetic acid (Mouse Whittle method, method C

Using ddy male mice, each test group consisted of 4 or 5 mice. A test compound was mixed with Tween 80 [polyoxyethylenesorbitan monooleate (manufactured by Nacalai Tesque K.K.)], and distilled water was added thereto to obtain a 2% Tween 80 suspension, or it was dissolved in the form of a salt in water to obtain an aqueous solution. A test compound was orally administered, and upon expiration of one hour from the administration, 0.7% acetic acid was intraperitonially injected to each mouse in an amount of 0.1 ml/10 g, and at the same time, 2% brilliant blue was intravenously injected into the tail vein in an amount of 0.1 ml/20 g. Thirty minutes after the injection of brilliant blue, the cervical vertebrae were dislocated under anesthesia by chloroform, and the abdorminal cavity was washed with 5 ml of a physiological saline. The washing solution was subjected to centrifugal separation of 3,000 rpm for 10 minutes, and the amount of the dye in the supernatant was measured at 600 nm absorbance by Microplate ELISA Reader (Model 2550EIA Reader, manufactured by Bio-Rad Laboratories). The inhibition rate of the amount of leaked dye in the group in which a test compound was administered relative to the control group was obtained by the following formula. The results are shown in Table 8. ##EQU3##

C: Amount of leaked dye in the group to which is a test compound was administered.

D: Amount of leaked dye in the control group.

                  TABLE 8                                                          ______________________________________                                                                    Inhibition                                          Compound No.   Dose (mg/kg)                                                                               rate (%)                                            ______________________________________                                          1             50          46                                                   2             20          51                                                   3             50          58                                                   4             50          43                                                   5             50          53                                                   7             20          53                                                   8             20          48                                                   9             50          81                                                  10             25          53                                                                 10          42                                                  11             100         49                                                  13             100         57                                                  15             50          41                                                  16             20          55                                                  17             50          31                                                  18             25          49                                                  20             20          48                                                  22             20          81                                                                 10          39                                                  23             20          33                                                  39             20          53                                                  41             100         85                                                  43             20          48                                                  45             20          29                                                  47             20          72                                                                 10          46                                                  49             20          50                                                  55             25          59                                                  57             20          43                                                  63             10          41                                                  78             20          51                                                                 10          32                                                  79             20          67                                                  86             20          42                                                  87             10          28                                                  93             20          47                                                                 10          40                                                  94             20          71                                                  101            20          46                                                  120            20          43                                                  251            20          43                                                  ______________________________________                                    

TEST EXAMPLE 4

Inhibitory activity on increased vascular permeability induced by acetic acid (Rat Whittle method, method D

Using SD (Crj: CD) male rats, each test group consisted of from 3 to 5 rats. A test compound was mixed with Tween 80 [polyoxyethylenesorbitan monooleate (manufactured by Nacalai Tesque K.K.)], and distilled water was added thereto to obtain a 2% Tween 80 suspension, or it was dissolved in the form of a salt in water to obtain an aqueous solution. A test compound was orally administered, and one hour later, 0.7% acetic acid was intraperitonially injected to each rat in an amount of 0.05 ml/10 g, and at the same time, 2% brilliant blue was intravenously injected into the tail vein in an amount of 0.05 ml/20 g. Thirty minutes after the injection of brilliant blue, the cervical vertebrae were dislocated under anesthesia by chloroform, and the abdorminal cavity was washed with 10 ml of a physiological saline. The washing solution was subjected to centrifugal separation at 3,000 rpm for 10 minutes, and the amount of the dye in the supernatant was measured at 600 nm absorbance by Microplate ELISA Reader (Model 2550EIA Reader, manufactured by Bio-Rad Laboratories). The inhibition rate of the amount of leaked dye in the group to which a test compound was administered relative to the control group was obtained from the following formula, and the results are shown in Table 9. ##EQU4##

C: Amount of leaked dye in the group to which a test compound was administered.

D: Amount of leaked dye in the control group.

                  TABLE 9                                                          ______________________________________                                                                    Inhibition                                          Compound No.   Dose (mg/kg)                                                                               rate (%)                                            ______________________________________                                          2             100         38                                                   3             100         75                                                  10             100         57                                                                 50          37                                                  16             100         96                                                  17             50          40                                                  19             50          34                                                  20             100         49                                                  22             100         58                                                  23             100         40                                                  43             50          72                                                  45             50          27                                                  46             50          31                                                  47             50          82                                                                 25          56                                                  49             50          30                                                  55             25          69                                                                 12.5        43                                                  57             50          47                                                  58             50          31                                                  60             50          72                                                  61             25          61                                                  63             50          39                                                                 25          31                                                  66             25          72                                                  69             25          48                                                  72             25          66                                                  78             50          55                                                                 25          40                                                  79             50          74                                                  80             50          35                                                                 25          33                                                  82             25          38                                                  86             50          37                                                  87             25          61                                                                 12.5        47                                                  93             50          71                                                                 25          54                                                  94             50          71                                                                 25          45                                                  98             50          32                                                  101            50          41                                                  113            50          67                                                  120            100         56                                                                 50          35                                                  121            12.5        31                                                  251            25          70                                                                 12.5        46                                                  ______________________________________                                    

TEST EXAMPLE 5

Inhibitory activity on carrageenin edema

Using Wister male rats (body weight: about 100 g), each test group consisted of 5 rats. A test compound was mixed with Tween 80 [polyoxyethylenesorbitan monooleate (manufactured by Nacalai Tesque K.K.)], and distilled water was added thereto to obtain a 2% Tween 80 suspension, or it was dissolved in the form of a salt in water to obtain an aqueous solution. Either the suspension or the aqueous solution was orally administered in an amount of 200 mg/kg, 100 mg/kg, 50 mg/kg or 25 mg/kg. One hour later, 0.1 ml of a 1% λ-carrageenin solution dissolved in a physiological saline was injected subcutaneously to the right hind paw of each rat to cause inflamation. Three hours later, the paw volume was measured by a paw volume measuring device (manufactured by Ugobasiee K.K.). A swelling volume was obtained from the difference from the value before the inflammation. The inhibition rate was calculated by the following formula, and the results are shown in Table 10. ##EQU5##

F: Average swelling volume in the group to which a test compound was administered.

E: Average swelling volume in the control group.

                  TABLE 10                                                         ______________________________________                                                                    Inhibition                                          Compound No.   Dose (mg/kg)                                                                               rate (%)                                            ______________________________________                                          2             100         17                                                   3             100         20                                                   5             100         37                                                  10             100         28                                                  11             100         24                                                  13             100         21                                                  16             100         24                                                  19             100         31                                                  22             100         29                                                  23             100         30                                                  25             200         27                                                  28             50          25                                                  39             100         25                                                  43             50          31                                                  45             50          23                                                  46             50          30                                                  47             50          41                                                  57             100         35                                                  60             50          27                                                  65             50          37                                                  66             50          31                                                  67             25          19                                                  69             50          25                                                  72             25          21                                                  73             50          20                                                  77             50          22                                                  78             50          26                                                  79             50          20                                                  80             50          29                                                  82             50          19                                                  86             50          27                                                  87             50          21                                                  91             50          23                                                  93             50          22                                                  94             50          23                                                  98             50          45                                                  101            50          24                                                  104            50          48                                                  106            50          19                                                  110            50          25                                                  113            50          26                                                  114            50          28                                                  120            50          27                                                  123            50          42                                                  125            50          23                                                  251            50          30                                                  259            50          17                                                  ______________________________________                                    

TEST EXAMPLE 6

Acute toxicity

Administration route: Intravenous injection

Using ddy male mice (body weight: 25-30 g), each test group consisted of 5 mice. A test compound was dissolved in the form of a sodium salt in a physiological saline or in a 5% glucose aqueous solution, and intravenously injected in an amount of 0.1 ml/10 g body weight. After the injection, the mortality rate was obtained over one week, and the median lethal dose LD₅₀ (mg/kg) was determined. The results are shown in Table 11.

                  TABLE 11                                                         ______________________________________                                         Compound No.   LD.sub.50 (mg/kg)                                               ______________________________________                                          1             100˜150                                                    2             50˜100                                                     3             >100                                                             8             >25                                                              9             >150                                                            10             50˜100                                                    11             >150                                                            12             >150                                                            13             >70                                                             15             100˜150                                                   16             >100                                                            17             50˜100                                                    18             >150                                                            19             50˜100                                                    21             >75                                                             22             >100                                                            24             >150                                                            40             50˜100                                                    43             78                                                              45             98                                                              47             58                                                              49             175                                                             55             237                                                             57             83                                                              60             >60                                                             61             >80                                                             63             >130                                                            68             >80                                                             73             >80                                                             77             >80                                                             78             >60                                                             80             >80                                                             86             >40                                                             87             75                                                              91             >80                                                             106            >20                                                             120            83                                                              251            65                                                              ______________________________________                                    

TEST EXAMPLE 7

Effects against acute pancreatitis

Using Crj-CD male rats (for Compound No. 19, rats having a body weight of from 371 to 484 g were used, and for Compound No. 10, rats having a body weight of from 444 to 574 g were used), each test group consisted of 3 rats. An experimental acute pancreatitis model was prepared by a closed duodenal loop method under anesthesia with halothane (manufactured by Hoechst Japan) and nitrous oxide (manufactured by Sumitomo Seika K.K.) applied by means of a general inhalation anesthesia machine (Model EM-2 and halothane evaporator F-Model). Then, Compound No. 19 or Compound No. 10 was continuously intravenously injected into the tail vein in an amount of 50 mg per kg or 40 mg per kg, respectively, at a rate of 0.05 ml per minute by means of a pump (Technicon AA II Proportioning Pump III, manufactured by Technicon Instruments Corporation). No injection was made to a control group. Gross pathological examination was conducted upon expiration of 6 hours after the ventrotomy in the case of the test group to which Compound No. 19 was administered, or upon expiration of 3 hours after the ventrotomy in the case of the test group to which Compound No. 10 was administered. As a result, as shown in the following Table 12, the groups to which the compounds of the present invention were administered, show distinct usefulness for treating acute pancreatitis.

                  TABLE 12                                                         ______________________________________                                                      Pancreatic                                                                     hemorrhage Pancreatic                                                          Petechia   edema                                                                         Distribu-      Distribu-                                Groups         Grade   tion     Grade tion                                     ______________________________________                                         Control group  ++      ++       ++    ++                                       (against the group                                                                            ++      ++       +++   ++                                       to which Compound No.                                                                         +++     +++      +++   ++                                       19 was administered)                                                           Group to which -       -        +     +                                        Compound No. 19                                                                               -       -        ++    ++                                       was administered                                                                              -       -        +     +                                        Control group  ++      ++       ++    ++                                       (against the group                                                                            +       +        ++    ++                                       to which Compound No.                                                                         ±    ±     ++    ++                                       10 was administered)                                                           Group to which ±    ±     ±  ±                                     Compound No. 10                                                                               -       -        +     +                                        was administered                                                                              +       +        ++    +                                        ______________________________________                                          Grade of pancreatic lesions                                                    -:No significant lesions, ±: Minimal, +: Light, ++: Moderate, +++:          Marked                                                                         Distribution of pancreatic lesions                                             -: No significant lesions, ±˜+++: Focaldiffuse                  

TEST EXAMPLE 8

Effects against acute pancreatitis

Using Crj-CD male rats, each test group consisted of 3 rats. An experimental acute pancreatitis model was prepared by a closed duodenal loop method under anethesia with halothane (manufactured by Hoechst Japan) and nitrous oxide (manufactured by Sumitomo Seika K.K.) applied by a general inhalation anesthesia machine (Model EM2 and halothane evaporator F-Model). Each compound (subjected to the test in the form of a sodium salt) was continuously intravenously injected into the tail vein in an amount of 0.4 ml/100 g to 0.6 ml/100 g at a rate of 0.05 ml per minute by a pump (Technicon AA II Proportioning Pump III, manufactured by Technicon Instruments Corporation) or rapidly intravenously injected. No injection was made to a control group. Gross pathological examination was conducted upon expiration of 6 hours after the ventrotomy in the case of the group to which the compound was administered. With respect to each of four lesions among pancreatic lesions i.e. petechia, ecchymosis, pancreatic necrosis and abdominal fatty necrosis, the grade and the distribution of lesions were scored with five grades of 0, 0.5, 1, 2 and 3 (severe lesions are 3). The sum of all lesions was designated as scores of pancreatitis lesions, and the sum of the score of petechia and the score of ecchymosis only was designated as scores of hemorrhagic lesions. The pancreatitis inhibition rate (%) and the hemorrhage inhibition rate (%) were obtained by the following formulas, and the results are shown in Table 13. ##EQU6##

H: Scores of pancreatitis lesions of the group to which a test compound was administered.

G: Scores of pancreatitis lesions of the control group. ##EQU7##

J: Scores of hemorrhagic lesions of the group to which a test compound was administered.

I: Scores of hemorrhagic lesions of the control group.

                  TABLE 13                                                         ______________________________________                                                        Dose                                                            Compound No.   (mg/kg)    *1     *2                                            ______________________________________                                          1             10         66     49                                             2             26*        46                                                    3             10         49     51                                             9             10         36     21                                            11             23*        52                                                   13             23*        100                                                  14             19*        52                                                   15             10         45     61                                            16             20*        52                                                   17             20*        73                                                   21             27*        57                                                   24             11*        68                                                   34             10         30     30                                            35             10         35     35                                            43             20*        81                                                   45             25*        62                                                   46             46*        36                                                   47             20*        68                                                   49             42*        68                                                   55             40*        65                                                   57             20*        60                                                   58             10         70     51                                            60             10         92     94                                            61             10         79     64                                            62             10         45     61                                            63             10         83     66                                            64             10         60     68                                            65             10         67     74                                            66             10         53     63                                            68             10         74     77                                            72             10         62     32                                            73             10         74     79                                            74             10         66     67                                            77             10         66     70                                            78             10         96     91                                            79             10         23     39                                            80             10         11     8                                             81             10         49     58                                            83             10         53     51                                            85             10         57     67                                            86             10         87     85                                            87             10         83     87                                            93             10         70     70                                            94             10         11     11                                            97             10         35     35                                            106            10         96     97                                            107            10         63     61                                            113            10         41     36                                            114            10         32     27                                            117            10         30     30                                            120            24*        100                                                  122            10         51     51                                            123            10         56     56                                            124            10         51     51                                            251            10         79     80                                            ______________________________________                                          Note: Symbol * in the column for the "Dose" indicates a case of continuou      intravenous injection, and no symbol indicates a case of single                intravenous injection. *1: Inhibition rate of hemorrhagic lesions (%) *2:      Inhibition rate of pancreatitis lesions (%)                              

To administer the compound of the present invention for the treatment of the above-mentioned diseases caused by phospholipase A₂, it is formulated alone or together with a pharmaceutically acceptable carrier into a drug composition suitable for peroral, or parenteral administration, such as a tablet, a powder, a capsule, a granule, an injection drug, an ointment, an inhalant or a suppository, and it is administered in the form of such a drug formulation.

As a drug formulation suitable for peroral administration, a solid composition such as a tablet, a capsule, a powder, a granule or a troach; or a liquid composition such as a syrup suspension, may be mentioned. The solid composition such as a tablet, a capsule, a powder, a granule or a troach may contain a binder such as fine crystalline cellulose, gum arabic, tragacanth gum, gelatine or polyvinyl chloride; an excipient such as starch, lactose or carboxymethyl cellulose; a disintegrator such as arginic acid, corn starch or carboxymethyl cellulose; a lubricant such as magnesium stearate, light silicic anhydride or colloidal silicon dioxide; a sweetener such as sucrose; or a flavoring agent such as peppermint or methyl salicylate. The liquid composition such as a syrup or a suspension may contain sorbitol, gelatine, methyl cellulose, carboxymethyl cellulose, a vegetable oil such as a peanut oil, an emulsifier such as lecithin as well as a sweetener, a preservative, a colorant or a flavoring agent, as the case requires. Such a composition may be provided in the form of a dried formulation. These formulations preferably contain from 1 to 95% by weight of the active compound.

A drug formulation suitable for parenteral administration may, for example, be an injection drug. The injection drug may be prepared by dissolving the compound in the form of a salt in usual water for injection, or may be formulated into a formulation suitable for injection such as a suspension or an emulsion (in a mixture with a pharmaceutically acceptable oil or liquid). In such a case, it may contain benzyl alcohol as an antibacterial agent, ascorbic acid as an antioxidant, a pharmaceutically acceptable buffer solution or a reagent for adjusting the osmotic pressure. Such an injection drug preferably contains from 0.1 to 8% by weight of the active compound.

A drug formulation suitable for topical or per rectal administration may, for example, be an inhalant, an ointment or a suppository. The inhalant may be formulated by dissolving the compound of the present invention alone or together with a pharmaceutically acceptable inert carrier in an aerosol or nebulizer solution, or may be administered to the respiratory airway in the form of fine powder for inhalation. In the case of fine powder for inhalation, the particle size is usually not more than 50 μm, preferably not more than 10 μm. Such an inhalant may be used, if necessary, in combination with other antiasthematic agent or bronchodilator.

An ointment may be prepared by a conventional method by an addition of a commonly employed base or the like. The ointment preferably contains from 0.1 to 30% by weight of the active compound.

The suppository may contain a carrier for formulation which is well known in this field, such as polyethylene glycol, lanolin, cacao butter or fatty acid triglyceride. The suppository preferably contains from 1 to 95% by weight of the active compound.

The above-mentioned drug compositions suitable for peroral, parenteral, topical or per rectal administration, may be formulated by conventional methods so that after administration to a patient, the active component will be rapidly discharged, gradually discharged or belatedly discharged.

The dose of the compound of the present invention varies depending upon the type of the compound, the administration method, the condition of the patient or the animal to be treated. The optimum dose and the number of administration under a specific condition must be determined by the judgement of a competent doctor. Usually, however, a daily dose to an adult is from about 0.01 g to about 10 g, preferably from about 0.05 g to about 5 g. In the case of the above inhalation method, the dose of the compound of the present invention is preferably from about 0.01 mg to about 100 mg per administration.

Now, specific Formulation Examples of the phospholipase A₂ inhibitor, the anti-inflammatory agent or the anti-pancreatitis agent of the present invention will be given.

FORMULATION EXAMPLE 1

(tablet)

    ______________________________________                                         (1) Compound No. 30                                                                               200 mg                                                      (2) Lactose        150 mg                                                      (3) Starch          30 mg                                                      (4) Magnesium stearate                                                                             6 mg                                                       ______________________________________                                    

The above composition is tabletted so that the components (1) to (4) constitute one tablet.

FORMULATION EXAMPLE 2

(powder or microgranule)

    ______________________________________                                         (1) Compound No. 35           200 mg                                           (2) Sugar ester (DK ester F-160, manufactured by                                                             180 mg                                               Daiichi Kogyo)                                                             (3) Surfactant (Dekagreen 1-L, manufactured by                                                                15 mg                                               Nikko Chemicals)                                                           (4) Light silicic anhydride    25 mg                                           ______________________________________                                    

The component (1) is wet-pulverized in an aqueous solution containing 5% of the component (3). Then, 180 mg of the component (2) is added thereto, and the mixture is freeze-dried. The dried product is pulverized and mixed with the component (4).

The mixture is formed into a powder or microgranule. Such a powder or microgranule may be sealed in a capsule to obtain a capsule drug.

FORMULATION EXAMPLE 3

(hard gelatine capsule)

    ______________________________________                                         (1) Sodium salt of Compound No. 10                                                                    250 mg                                                  (2) Starch             200 mg                                                  (3) Magnesium stearate  10 mg                                                  ______________________________________                                    

The components (1) to (3) is packed in a hard gelatine capsule to obtain a hard gelatine capsule drug.

FORMULATION EXAMPLE 4

(injection drug)

    ______________________________________                                         (1) Sodium salt of Compound No. 19                                                                     1 g                                                    (2) Glucose             10 g                                                   (3) Distilled water for injection                                                                     200 ml                                                  ______________________________________                                    

The components (1) to (3) are formulated into an injection drug in accordance with a usual method for preparation of an injection drug.

FORMULATION EXAMPLE 5

(ointment for external skin application)

    ______________________________________                                         (1) Sodium salt of Compound No. 10                                                                       5 g                                                  (2) White vaseline        25 g                                                 (3) Stearyl alcohol       22 g                                                 (4) Propylene glycol      12 g                                                 (5) Sodium lauryl sulfate 1.5 g                                                (6) Ethyl para-hydroxybenzoate                                                                           0.025 g                                              (7) Propyl para-hydroxybenzoate                                                                          0.015 g                                              (8) Purified water        100 g                                                ______________________________________                                    

The components (1) to (8) are formulated into an ointment for external skin application by a usual method for preparation of an ointment. 

We claim:
 1. A method of treating rheumatoid arthritis by administering an effective amount of a diaminotrifluoromethylpyridine derivative of the formula (I) or its salt: ##STR341## wherein X is --CW¹ R¹, --COCOR², --CW¹ NHCOR², --C(═W¹)W² R³ or --CW¹ N(R⁴), R⁵, and Y is alkyl, --CW³ R⁶, --COCOR⁷, --NHCOR⁷, --C(═W³)W⁴ R⁸, --(NH)_(m) SO₂ R⁹, --(NH)_(m) SO₂ OR¹⁰ or --(NH)_(m) SO₂ N(R¹¹)R¹², wherein each of R¹, R⁶ and R⁹, which are independent from one another, is a chain hydrocarbon group which may be substituted, a monocyclic hydrocarbon group which may be substituted, a polycyclic hydrocarbon group which may be substituted, a monocyclic heterocycle group which may be substituted or a polycyclic heterocycle group which may be substituted, each of R² and R⁷, which are independent from each other, is alkyl which may be substituted, alkoxy which may be substituted, phenyl which may be substituted or phenoxy which may be substituted, each of R³, R⁸ and R¹⁰, which are independent from one another, is alkyl which may be substituted, alkenyl which may be substituted, alkynyl which may be substituted, cycloalkyl which may be substituted, phenyl which may be substituted or benzyl which may be substituted, each of R⁴, R⁵, R¹¹ and R¹², which are independent from one another, is alkyl which may be substituted, each of W¹, W², W³ and W⁴, which are independent from one another, is an oxygen atom or a sulfur atom, and m is 0 or 1, provided that a combination wherein one of X and Y is --COCF₂ X¹ wherein X¹ is a hydrogen atom, a halogen atom, alkyl or haloalkyl, and the other is --COCF₂ X² wherein X² is a hydrogen atom, a halogen atom, alkyl, haloalkyl or alkylcarbonyl, or --COOX³ wherein X³ is alkyl which may be substituted or phenyl which may be substituted, is excluded.
 2. The method according to claim 1, wherein said hydrocarbon group for each of R¹, R⁶ and R⁹ is alkyl, alkenyl or alkynyl; said monocyclic hydrocarbon group for each of R¹, R⁶ and R⁹ is cycloalkyl, cycloalkenyl, or phenyl; said polycyclic hydrocarbon group for each of R¹, R⁶ and R⁹ is a condensed polycyclic hydrocarbon group such as naphthyl, tetrahydronaphthyl or indanyl, or a bridged polycyclic hydrocarbon group such as adamantyl, noradamantyl, norbornanyl or norbornanonyl; said monocyclic heterocycle group for each of R¹, R⁶ and R⁹ is pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolinyl, pyrrolidinyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, pyrazolinyl, hydantoinyl, oxazolinyl, isoxazolinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, dioxolanyl, dithiolanyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, dihydropyridyl, tetrahydropyridyl, piperidinyl, dihydrooxopyridazinyl, tetrahydrooxopyridazinyl, dihyrooxopyrimidinyl, tetrahydrooxopyrimidinyl, piperazinyl, dihydropyranyl, tetrahydropyranyl, dioxanyl, dihydrodithinyl, dithianyl or morphorinyl; said polycyclic heterocycle group for each of R¹, R⁶ and R⁹ is a condensed polycyclic heterocycle group such as thienothienyl, dihydrocyclopentathienyl, indolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzimidazolyl, tetrahydrobenzothienyl, dihydrobenzofuranyl, tetrahydrobenzisoxazolyl, benzodioxolyl, quinolinyl, isoquinolinyl, benzodioxanyl or quinoxalinyl, or a bridged polycyclic heterocycle group such as quinuclidinyl; the substituent for each of the chain hydrocarbon group which may be substituted for each of R¹, R⁶ and R⁹, the alkyl which may be substituted and the alkoxy which may be substituted for each of R² and R⁷, the alkyl which may be substituted, the alkenyl which may be substituted and the alkynyl which may be substituted for each of R³, R⁸ and R¹⁰, the alkyl which may be substituted for each of R⁴, R⁵, R¹¹ and R¹², and the alkyl which may be substituted for X³, is a halogen atom, alkoxy, haloalkoxy, alkylthio, cycloalkyl, cycloalkoxy, cycloalkenyl, cycloalkenyloxy, alkoxycarbonyl, alkylcarbonyl, alkylcarbonyloxy, aryl, aryloxy, arylthio, amino or alkyl-substituted amino; and the substituent for each of the monocyclic hydrocarbon group which may be substituted, the polycyclic hydrocarbon group which may be substituted, the monocyclic heterocyclic group which may be substituted and the polycyclic heterocycle group which may be substituted for each of R¹, R⁶ and R⁹, the phenyl which may be substituted and the phenoxy which may be substituted for each of R² and R⁷, the cycloalkyl which may be substituted, the phenyl which may be substituted and the benzyl which may be substituted for each of R³, R⁸ and R¹⁰, and the phenyl which may be substituted for X³, is a halogen atom, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, cycloalkyl, cycloalkoxy, cycloalkenyl, cycloalkenyloxy, alkoxycarbonyl, alkylcarbonyl, alkylcarbonyloxy, aryl, aryloxy, arylthio, amino, alkyl-substituted amino, cyano or nitro.
 3. The method according to claim 1, wherein X is --CW¹ R¹ or --C(═W¹)W² R³, and Y is --SO₂ R⁹.
 4. The method according to claim 1, wherein X is --CW¹ R¹ or --C(═W¹)W² R³, wherein R¹ is alkyl which may be substituted, alkenyl which may be substituted, cycloalkyl which may be substituted, cycloalkenyl which may be substituted, phenyl which may be substituted, tetrahydronaphthyl which may be substituted, indanyl which may be substituted or thienyl which may be substituted, and R³ is alkyl which may be substituted, and Y is --SO₂ R⁹, wherein R⁹ is alkyl which may be substituted, alkenyl which may be substituted, cycloalkyl which may be substituted, cycloalkenyl which may be substituted or phenyl which may be substituted.
 5. The method according to claim 1, wherein X is --CW¹ R¹ or --C(═W¹)W² R³, wherein R¹ is alkyl, haloalkyl, alkenyl, haloalkenyl, cycloalkyl, halogen-substituted cycloalkyl, phenyl, halogen-substituted phenyl, alkyl- or haloalkyl-substituted phenyl, or alkoxy- or haloalkoxy-substituted phenyl, and R³ is alkyl or haloalkyl, and Y is --SO₂ R⁹, wherein R⁹ is alkyl, haloalkyl, phenyl, halogen-substituted phenyl, alkyl- or haloalkyl-substituted phenyl, or alkoxy- or haloalkoxy-substituted phenyl.
 6. The method according to claim 1, wherein said diaminotrifluoromethylpyridine derivative is at least one derivative selected from the group consisting of N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclohexanecarboxamide, N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-5-indanecarboxamide, N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)acetoxyacetamide, N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)crotonamide, N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-2-thiophenecarboxamide, N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-3-trifluoromethylbenzamide, N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)-3-fluorobenzamide, N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-6-(1,2,3,4-tetrahydronaphthalene)carboxamide, N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)crotonamide and N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-3-(2-thienyl)acrylamide. 